Ò

PAIN 153 (2012) 1006–1014

www.elsevier.com/locate/pain

Changes in regional gray matter volume in women with chronic pelvic pain:
A voxel-based morphometry study
Sawsan As-Sanie a, Richard E. Harris b, Vitaly Napadow c, Jieun Kim c, Gina Neshewat a, Anson Kairys b,
David Williams b, Daniel J. Clauw b, Tobias Schmidt-Wilcke b,d,⇑
a
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA
b
Department of Anesthesiology, Chronic Pain and Fatigue Research Center, University of Michigan, Ann Arbor, MI 48109, USA
c
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA
d
Department of Neurology, University of Tübingen, Tübingen 07071, Germany

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

a r t i c l e i n f o a b s t r a c t

Article history: Chronic pelvic pain (CPP) is a highly prevalent pain condition, estimated to affect 15%–20% of women in
Received 16 July 2011 the United States. Endometriosis is often associated with CPP, however, other factors, such as preexisting
Received in revised form 28 December 2011 or concomitant changes of the central pain system, might contribute to the development of chronic pain.
Accepted 31 January 2012
We applied voxel-based morphometry to determine whether women with CPP with and without endo-
metriosis display changes in brain morphology in regions known to be involved in pain processing. Four
subgroups of women participated: 17 with endometriosis and CPP, 15 with endometriosis without CPP, 6
Keywords:
with CPP without endometriosis, and 23 healthy controls. All patients with endometriosis and/or CPP
Chronic pelvic pain
Endometriosis
were surgically confirmed. Relative to controls, women with endometriosis-associated CPP displayed
Voxel-based morphometry decreased gray matter volume in brain regions involved in pain perception, including the left thalamus,
Thalamus left cingulate gyrus, right putamen, and right insula. Women with CPP without endometriosis also
Cingulate cortex showed decreases in gray matter volume in the left thalamus. Such decreases were not observed in
patients with endometriosis who had no CPP. We conclude that CPP is associated with changes in regio-
nal gray matter volume within the central pain system. Although endometriosis may be an important risk
factor for the development of CPP, acting as a cyclic source of peripheral nociceptive input, our data sup-
port the notion that changes in the central pain system also play an important role in the development of
chronic pain, regardless of the presence of endometriosis.
Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

1. Introduction the presence or severity of ‘‘peripheral pathology’’. For example,

Chronic pelvic pain (CPP) is defined as ‘‘non-cyclic pain of 6 or
more months’ duration that localizes to the anatomic pelvis, ante-
rior abdominal wall at or below the umbilicus, the lumbosacral
back, or the buttocks, and is of sufficient severity to cause func-
tional disability or lead to medical care’’ [1]. CPP is estimated to af-
fect 15%–20% of women in the United States, with direct health
care costs approaching $2.8 billion per year [1,22]. It is the primary
indication for 10% of outpatient gynecology visits, 40% of diagnos-
tic laparoscopies, and 12%–17% of hysterectomies performed annu-
ally [18,46].
Despite its high prevalence and negative impact, little is known
about the mechanisms underlying CPP. As in most other chronic
pain syndromes, its pathogenesis cannot be entirely explained by
⇑ Corresponding author at: Department of Neurology, Hertie-Institut für klinische
Hirnforschung, University of Tübingen, 72076 Tübingen, Germany.
E-mail address: tobias.schmidt-wilcke@med.uni-tuebingen.de (T. Schmidt-Wilcke).
in women with endometriosis-associated CPP, there is little, if
any, association between the severity of pain and the extent of
endometriosis [5,26,43]. Medical and surgical therapies are not al-
ways effective and pain frequently recurs, often without evidence
of residual disease [35,38,42]. Against this background, endometri-
osis must be viewed as an important but insufficient risk factor for
the development of CPP.
Pain in many other chronic pain syndromes has been shown to
be related to central nervous system (CNS) amplification of pain
processing, which often occurs in the absence of injury or inflam-
mation of peripheral structures [7,11,12,14,16,23]. From a neuro-
biological perspective, the mechanisms contributing to pain
amplification and chronicity are heterogeneous and likely occur
at various levels of the nervous system. In line with this evidence,
structural alterations in brain regions associated with pain percep-
tion and modulation have also been identified in patients with
chronic pain. The most reproducible finding is a decrease in gray
matter density/volume in the thalamus, cingulate cortex, and the

0304-3959/$36.00 Ó 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.pain.2012.01.032
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S. As-Sanie et al. / PAIN 153 (2012) 1006–1014
insular cortex (IC) [29,30]. It has been postulated that such changes
in regional brain morphology may be responsible not only for the
evolution and/or maintenance of the chronic pain state, but might
also contribute to other common comorbid clinical traits, such as
mood disorders and cognitive impairment [9,21,32].
Therefore, studies of brain anatomy and function might also be
important for understanding the pathogenesis of CPP. The primary
aim of this study was to use voxel-based morphometry (VBM) to
determine whether women with CPP display changes in regional
brain morphology and whether such changes are present in wo-
men with similar pelvic pathology without CPP. We investigated
3 patient subgroups: CPP and endometriosis, endometriosis but
no CPP, and CPP but no endometriosis, and compared each to
healthy controls. We hypothesized that CPP is associated with
decreased gray matter volume in brain regions associated with
pain perception and modulation, and that these differences are
associated with the experience of chronic pain rather than the
presence or absence of endometriosis. If this hypothesis is correct,
then CPP patients (with and without endometriosis) should show
gray matter changes in structures within the pain system relative
to controls, and these changes would not be present in endometri-
osis patients without CPP.
2. Methods
2.1. Subjects
Four cohorts of participants were included: 17 women with
endometriosis-associated CPP (EndoPain), 15 women with
‘‘pain-free’’ endometriosis (Endo£Pain, for a definition of
‘‘pain-free’’ see below), 6 women with CPP but no evidence of
endometriosis (£EndoPain group, surgically confirmed), and 26
healthy women (HCs [healthy controls]). For details, see Tables 1
and 2 and Fig. 1. All participants were reproductive-age women
(18-52 years) who had not undergone prior hysterectomy or bilat-
eral oophorectomy. Women with endometriosis were recruited
from a tertiary-care endometriosis and pelvic pain referral center,
as well as through advertisement to the local community. Inclusion
criteria for endometriosis participants included a history of surgi-
cally confirmed endometriosis within 3 years of study participa-
tion. Most participants received their surgical diagnosis at
another medical institution. Operative reports were reviewed by
a gynecologist with significant experience in the surgical evalua-
tion of endometriosis (S.A.) blinded to study results, and endome-
triosis was assigned a stage according to the revised American
Fertility Society endometriosis scoring system [28]. Surgical
pathology was documented when available but not required for
participation because pathologic confirmation was not routinely
performed in all participants. Potential participants with a history
of endometriosis were screened by a telephone interview and were
invited to participate only if they fell within 1 of 2 categories of
pelvic pain severity: 1) chronic pelvic pain or 2) ‘‘pain-free’’ endo-
metriosis. CPP was defined as moderate to severe pelvic pain that is
P4 on a 0-10 verbal rating scale for >6 months duration, and was
noncyclic, occurring for at least 14 days of each month, not just
limited to the time of menstrual bleeding. Pelvic pain was localized
to the anatomic pelvis, and could include but was not limited to
only symptoms of dyspareunia (pain with intercourse), dyschezia
(pain with bowel movements), or focal low back pain. ‘‘Pain-free’’
endometriosis was defined as the absence of any prior history of
chronic pelvic pain and the absence of significant dysmenorrhea,
defined as pelvic pain during menstruation that is P4 on a 0-10
verbal rating scale occurring for 5 or more days of each menstrual
cycle (ie, all study participants falling into the Endo£Pain group
had at maximum 4 days of mild pain associated with menses). This
1007
study also included data on 6 participants with CPP but no evi-
dence of endometriosis (£EndoPain). These women fulfilled all
clinical criteria of CPP, had no prior surgical history of endometri-
osis, had undergone a diagnostic laparoscopy within 3 years of
study participation, and had no surgical evidence of endometriosis
or pelvic adhesions at the time of surgical exploration. No other
anatomic sources of pain could be identified in these patients.
Using standardized criteria, all women with endometriosis and/
or CPP were formally screened for and excluded from participation
if they had one or more of the following chronic pain syndromes
thought to be associated with a central nervous system abnormal-
ity in pain processing: fibromyalgia, chronic fatigue syndrome,
interstitial cystitis, chronic low back pain unrelated to pelvic pain,
or temporomandibular disorder. Women with CPP had to discon-
tinue opioid analgesia for 72 hours prior to the magnetic resonance
imaging (MRI) visit.
HCs completed standardized case report forms to assess their
medical history, surgical history, medication use, and any pain
symptoms. All HCs were pain-free women without symptoms
of dysmenorrhea, no known history of endometriosis, and no his-
tory of chronic pain (including pelvic pain or discomfort). All HCs
were formally screened in a similar fashion to endometriosis par-
ticipants and did not meet criteria for any of the chronic pain
syndromes previously defined; and they did not have a history
of chronic, recurrent headaches or irritable bowel syndrome. Wo-
men with current symptoms of major depressive disorder, bipo-
lar disorder, general anxiety disorder (according to Diagnostic and
Statistical Manual of the American Psychiatric Association IV crite-
ria) [3] and those currently on antidepressants for any indication
were excluded. HCs were recruited from ongoing studies using
the same functional MRI protocol used in this study. Because
the mean age of endometriosis/CPP subgroups was significantly
different, each subgroup of endometriosis/CPP patients was com-
pared to an age-matched subset of HCs in a 1:1 or 2:1 ratio
(Fig. 1).
All participants had to be free of contraindications for an MRI
study as determined by a health questionnaire, and were right-
handed to simplify brain mapping. In order to minimize the influ-
ence of menstrual cycle variability on study results, all study visits
were performed between days 2 and 10 of the menstrual cycle in
women who were not using hormonal contraceptives. Additional
exclusion criteria for all participants included a severe physical
impairment (eg, complete blindness, deafness, paraplegia), coexis-
ting physical injury (eg, sprained ankle, neck injury), comorbid
medical illnesses (eg, morbid obesity, autoimmune diseases, car-
diopulmonary disorders, uncontrolled endocrine or allergic disor-
ders, or malignancy within 2 years), any present psychiatric
disorder involving a history of psychosis, current suicide risk or at-
tempt within 2 years of the study, substance abuse within 2 years,
a pending status associated with disability or the receipt of disabil-
ity compensation, being pregnant, lactating, or menopausal
(defined as no menses for >1 year unrelated to exogenous hor-
monal suppression), or a contraindication to undergoing MRI (eg,
metal implants, claustrophobia).
2.2. Clinical and experimental pain
Participants with endometriosis and/or CPP completed
additional standardized case report forms to assess their surgical
history, medication use, and the severity, pattern, and characteris-
tics of their pelvic pain. Measurements included numeric ratings
(0-10) of pelvic pain during their menses, and the average pelvic
pain intensity and unpleasantness in the last month measured
with the Gracely Box Scale (GBS; Fig. 2) [13]. The GBS is a numer-
ical scale that is used to evaluate pain intensity and unpleasantness
(GBS pelvic pain intensity and unpleasantness). This scale com-
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1008 S. As-Sanie et al. / PAIN 153 (2012) 1006–1014

Table 1
Demographic and psychophysical characteristics of participant subgroups.

Group 1: Endo Pain Group 2: Endo £Pain Group 3: £Endo Pain

EndoPain Controls P- Endo£Pain Controls P- £EndoPai n Controls P-
(n = 17) (n = 17) value (n = 15) (n = 14) value (n = 6) (n = 12) value
Demographics
Age (years) 26.1 ± 1.5⁄ 25.9 ± 1.6 0.92 36.8 ± 2.2⁄  36.2 ± 2.6 0.86 24.2 ± 1.9  24.8 ± 1.2 0.79
Race, white (%) 15 (88.2) 16 (94.1) 0.39 13 (86.7) 13 (92.9) 0.62 5 (83.3) 12 (100.0) 0.16
Currently using hormonal 10 (58.8) 9 (52.9) 0.61 4 (26.7) 3 (23.1) 0.83 4 (66.7) 5 (45.5) 0.40
contraceptive (%)
Clinical pain (see Table 2)
Experimental pressure pain testing
Faint pain (kg) 0.72 ± 0.48 1.08 ± 0.94 0.17 1.43 ± 1.56 1.04 ± 1.04 0.44 0.63 ± 0.43 1.10 ± 0.95 0.26
Mild pain (kg) 1.99 ± 1.06 2.67 ± 1.24 0.09 2.80 ± 1.42 2.60 ± 1.41 0.70 2.00 ± 0.90 2.99 ± 1.26 0.11
Slightly intense pain (kg) 3.06 ± 1.52⁄ 4.18 ± 1.62 0.05 4.44 ± 1.63⁄ 4.25 ± 1.62 0.76 3.23 ± 1.71 4.38 ± 1.91 0.24
Mood and physical function
Depression (CES-D) 12.5 ± 7.2⁄ 2.4 ± 2.8 <0.001 4.8 ± 6.5⁄ 1.0 ± 2.2 0.06 8.8 ± 2.6 1.2 ± 2.1 <0.001
Trait Anxiety (STPI) 18.3 ± 4.5 12.5 ± 2.3 <0.001 15.0 ± 4.0 12.3 ± 2.3 0.04 16.3 ± 3.9 12.5 ± 2.5 0.02
SF-36, physical component 40.7 ± 10.6⁄ 57.9 ± 2.1 <0.001 56.2 ± 3.6⁄  57.6 ± 2.1 0.24 39.1 ± 5.9  57.1 ± 3.2 <0.001

EndoPain, endometriosis with chronic pelvic pain; Endo£Pain, endometriosis without chronic pelvic pain; £EndoPain, chronic pelvic pain without endometriosis;
CES-D, Center for Epidemiologic Studies Depression Scale; STPI, State-Trait Personality Inventory.
In a first step, each patient group was compared to its age-matched healthy control group (P-values in columns 4, 7, and 10). Further analyses (t-tests) were performed
between patient groups; significant differences (P < 0.05, corrected for multiple comparisons) are marked as follows: ⁄ Endo£Pain vs EndoPain;   Endo£Pain vs
£EndoPain; à EndoPain vs £EndoPain.

prises 21 boxes, sequentially numbered beginning with 0 and end-
ing with 20. It is aligned vertically, with 0 representing the least
amount of pain. Descriptive words are arranged next to the num-
bers corresponding with increasing levels of pain intensity and
unpleasantness.
Prior to MRI scanning, experimental pain testing was conducted
on all participants using the multiple random staircase method
previously described by our group [14]. Pressure-pain values re-
quired to elicit faint pain (0.5 on the GBS, see below and Fig. 2),
mild pain (7.5 on the GBS), and slightly intense pain (13.5 on
GBS) pain were determined for every subject by applying associ-
ated pressures (1-10 kg/cm2 to the right or left thumb) as deter-
mined by the multiple random staircase method.
2.3. Depression, anxiety, and physical function
All participants completed standardized measures of depres-
sion, anxiety, and physical function. These values were used to
characterize the degree of psychological distress and function of
patient subgroups relative to healthy controls, and to determine
if such measures of distress correlate with changes in regional gray
matter (GM) volume. Depressive symptoms were measured with
the Center for Epidemiological Studies-Depression Scale, a 20-item
self-report inventory designed to assess depressive mood [27]. Par-
ticipants are asked to indicate how frequently they experienced
each set of symptoms during the past week. The total possible
score, ranging from 0 to 60, reflects both the number of symptoms
and the frequency of their occurrence. Trait anxiety was measured
using the 10-item Trait Anxiety scale from the State-Trait Person-
ality Inventory [36]. Scores range from 10 to 40, with higher values
indicating higher anxiety symptoms. Physical function and health
status were measured with the SF-36, and provides individual
summary scores for physical function and mental function [45].
The summary scores have been standardized to have a mean = 50,
SD = 10 in the general U.S. population, with larger values indicating
better function. All questionnaires were administered within
72 hours of the MRI scan.
Group differences between characteristics of patients and con-
trols and subgroups of patients were evaluated using Student’s t-
test and Pearson’s v2 test, as appropriate. The significance thresh-
old was set at P < 0.05. Overall group differences between charac-
teristics of 3 subgroups of endometriosis and pelvic pain patients
were evaluated with analysis of variance and Pearson’s v2 tests,
as appropriate. Further analysis between subgroups of patients
(Endo£Pain vs. EndoPain; Endo£Pain vs. £EndoPain;
and EndoPain vs. £EndoPain) was performed with Student’s
t-test and Pearson’s v2 tests. Results were thresholded at
P < 0.05, after performing a domain-specific correction for multiple
comparisons (Bonferroni; P < 0.05/number of domains), yielding a
threshold of P < 0.017 for 3 domains. Three domains included clin-
ical pain, experimental pain testing, and measures of mood/
function.
2.4. Scanning protocol
MRI was performed on a 3.0 Tesla GE Signa scanner (LX [VH3]
release, Neuro-optimized gradients; General Electric Company,
Fairfield, CT, USA). For each subject, a T1-weighted gradient echo
data set (repetition time 1400 ms, time to echo 5.5 ms, flip angle
20°, field of view 256  256, yielding 124 sagittal slices with a de-
fined voxel size of 1  1  1.2 mm) was acquired. An Eclipse 3.0 T
94 quadrature head coil was used. Inspection of individual T1 MR
images revealed no gross morphological abnormality for any
participant.
2.5. Preprocessing and statistical analysis of VBM data
The SPM5 software package (Functional Imaging Laboratories,
London, UK), running under MATLAB 7b, was used to preprocess
and analyze structural data [4]. Estimation of total GM volume, to-
tal white matter (WM) volume, and cerebrospinal fluid (CSF) was
performed by segmenting the original image into GM, WM, and
CSF, using the IBASPM toolbox (toolbox for automatic parcellation
of brain structures), provided by the Cuban Neuroscience Center
[2].
Preprocessing of structural images for VBM analyses was
performed using the VBM toolbox (VBM 5.1, provided by C. Gaser,
default settings), which involved spatial normalization, segmenta-
tion, and spatial smoothing (Gaussian kernel of 8 mm full width at
half maximum for GM images). Modulated images were used for
statistical analyses; correspondingly, GM and WM values are re-
ferred to as regional GM or WM volume. Significant regional differ-
ences in GM values between groups were identified applying
voxel-wise statistics within the general linear model (2-sample t-
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S. As-Sanie et al. / PAIN 153 (2012) 1006–1014
Table 2
Clinical characteristics of pelvic pain/endometriosis patients.
Group 1 Endo Pain
(n = 17)
Endometriosis stage (rAFS) at most recent surgery
I 11 (64.7)
II 3 (7.7)
III 1 (5.9)
IV 2 (11.8)
Pain duration, median years (95% CI) 5.5 (3.5-9.5)⁄
Months since most recent surgery for endometriosis or 17.9 ± 13.5
pelvic pain
Number prior surgeries for endometriosis or pelvic pain
1 11 (64.7)
P2 6 (35.3)
Number of pelvic pain days per month, median days (95% 25.0 (14.0-29.0)⁄
CI)
Measures of clinical pain intensity
Average pain intensity in last month (GBS, intensity) 14.8 ± 2.0⁄
Average pain unpleasantness in last month (GBS, 14.5 ± 2.1⁄
unpleasant)
Average pain intensity during menses (0-10) 8.8 ± 1.4⁄
EndoPain, endometriosis with chronic pelvic pain; Endo£Pain, endometriosis without chronic pelvic pain; £EndoPain, chronic pelvic pain without endometriosis;
ANOVA, analysis of variance; rAFS, Revised American Fertility Society endometriosis score; CI, confidence scale; GBS, Gracely box scale.
Post hoc analyses were performed to determine significant differences between subgroups, significant differences (P < 0.05, corrected for multiple comparisons) are marked
as follows: ⁄ Endo£Pain vs EndoPain;   Endo£Pain vs £EndoPain; à EndoPain vs £EndoPain.
test with age as nuisance variable, also referred to as parametric
cohort analysis).
As the EndoPain and the Endo£Pain group were 10 years
apart in age (group average), each group was analyzed with its
own age-adjusted HC group (ie, for the EndoPain group,
n = 17; and for the Endo£Pain group, n = 15). Each of these 2
HC groups were drawn from the pool of 23 HCs. Eight HC partici-
pants were included in both control groups. For the 6 £EndoPain
patients, we matched 12 HCs of the same age, 8 of which were in-
cluded in the previous HC comparison groups. With respect to the
small number of patients in this group, a nonparametric group
comparison was performed using the SnPM (Statistical nonPara-
metric Mapping) toolbox, which uses the general linear model
and voxel-wise statistics to construct pseudo t-statistic images,
and then assesses the data for significance using a nonparametric
multiple comparison procedure based on permutation testing (in
our case, 5000 permutations). Permutation tests are recommended
for designs with low degrees of freedom [24]. The following design
module was applied: 2 groups; 2-sample t-test; 1 scan per subject,
controlling for age. To avoid possible edge effects around the bor-
der between gray and white matter and to include only relatively
homogeneous voxels, we excluded all voxels with a GM matter va-
lue of <0.1 (maximum value of 1) for both parametric and nonpara-
metric tests.
Statistical maps were corrected for multiple comparisons on the
cluster level (P < 0.05, derived from an uncorrected voxel level
threshold of P < 0.001, with a cluster extent of 660 contiguous vox-
els), as estimated by AlphaSim, an application implemented in the
Analysis of Functional NeuroImages software (http://afni.nimh.-
nih.gov/afni/doc/manual/AlphaSim), which is based on a Monte
Carlo simulation (5000 simulations) applied to a whole brain mask
(including cortical GM, WM, CSF, brainstem, and cerebellum). As
we had a clearly defined a priori hypothesis, looking for GM
changes within structures of the pain system and pain modulatory
system (midbrain, thalamus, putamen, amygdala, somatosensory
cortex, insular cortex, cingulate cortex, and prefrontal cortex);
we allowed, in a second step for these regions, a relaxed cluster ex-
tent threshold of 200 contiguous voxels. Clusters with an extent
between 200 and 660 voxels outside the pain system are reported,
as these results could be interesting for future analyses, but will
not be further commented on (and should be regarded as uncor-
1009
Group 2 Endo £Pain Group 3 £Endo Pain ANOVA 3-group P-
(n = 15) (n = 6) value
4 (26.7) 0
1 (6.7) 0
7 (46.7) 0
2 (13.3) 0
0 (0,0)⁄  3.75 (0.90-9.9)  0.001
19.4 ± 14.7 10.7 ± 9.8 0.41
10 (66.7) 5 (83.3) 0.69
5 (33.3) 1 (16.7)
0 (0-0)⁄  25.0 (18.4-29.5)  <0.001
0.9 ± 1.9⁄  15.3 ± 2.7  <0.001
0.9 ± 2.1⁄  15.0 ± 3.0  <0.001
1.5 ± 2.8⁄  8.8 ± 1.3  <0.001
rected). Anatomical labeling of brain regions was performed using
the SPM5 extension xjview (http://www.alivelearn.net/xjview8/).
To further explore behavioral relevance of changes in regional
GM volume, we performed correlation analyses, extracting the
eigenvariate from the GM clusters identified in the cohort analyses.
This yielded an average GM value for that region in each person;
values were then transferred to SPSS (Version 17; IBM Corporation,
Armonk, NY, USA), where we performed correlation analyses, cor-
relating extracted GM values with 3 domains of behavioral and
pain data:
(1) Clinical pain: pain intensity (visual analogue scale) on day of
functional MRI scan, GBS pelvic pain intensity and GBS pel-
vic pain unpleasantness in the last month, and duration of
CPP.
(2) Experimental pain: pressure needed to elicit faint (0.5 on the
GBS), mild (7.5 on the GBS), and/or slightly intense pain
(13.5 on the GBS).
(3) Mood and physical function measures: anxiety, depression,
and physical function component of SF-36.
For the £EndoPain group (n = 6) we performed Spearman’s
rank correlations due to the small sample size; within the other
2 groups (EndoPain and £EndoPain), Pearson correlations
were performed. Results were thresholded at P < 0.05, after per-
forming a domain-specific correction for multiple comparisons
(Bonferroni; P < 0.05/number of domains), yielding a threshold
P < 0.017 for all 3 domains. For explorative reasons, correlation
analyses were also performed within each group between GM
eigenvariates extracted from GM clusters, identified in the cohort
analyses, because correlations between GM values in remote brain
regions can be an indicator of structural connectivity [17]. No cor-
rections for multiple comparisons were applied in these analyses.
3. Results
3.1. Behavioral data: age, pain, pain thresholds, anxiety, and
depression
Descriptive data on age, race, and current hormonal contracep-
tive use is presented in Table 1. Generally, participants with CPP,
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1010 S. As-Sanie et al. / PAIN 153 (2012) 1006–1014
Fig. 1. Overview of study population. N, number; EndoPain, endometriosis with
chronic pelvic pain; Endo£Pain, endometriosis without chronic pelvic pain;
£EndoPain, chronic pelvic pain without endometriosis. ⁄ Each subgroup of
endometriosis/chronic pelvic pain group (groups 1-3) was compared to an age-
matched subset of healthy controls.
both with and without endometriosis (EndoPain and £Endo
Pain), were young women who were significantly younger than
women with endometriosis without CPP.
The surgical history and clinical pain experience of women with
endometriosis and/or CPP are presented in Table 2. Although more
advanced-stage endometriosis was found in the Endo£Pain
group when compared to the EndoPain group, there was no cor-
relation between endometriosis stage and any other clinical pain
characteristic (data not presented). When comparing the 2 sub-
groups of participants with CPP (EndoPain and £EndoPain),
Fig. 2. Gracely Box Scale (GBS) measures of pelvic pain intensity (left) and
unpleasantness (right).The GBS is a numerical scale that is used to evaluate pain
intensity and unpleasantness (GBS pelvic pain intensity and unpleasantness). This
scale comprises 21 boxes, sequentially numbered beginning with 0 and ending with
20. It is aligned vertically, with 0 representing the least amount of pain. Descriptive
words are arranged next to the numbers corresponding with increasing levels of
pain intensity and unpleasantness.
there was also no difference in median duration of pelvic pain
symptoms (P = 0.29), average number of pain days per month
(P = 0.42), and mean pain intensity before (P = 0.91) or during men-
ses (P = 0.98).
3.2. Results from voxel-based morphometry – cohort analyses and
correlations analyses
VBM analyses revealed several regions of GM volume changes
in various parts of the brain, while comparing each group to their
own matched HC group. In the EndoPain group, GM volume de-
crease (in comparison to the HC group) was observed in the left
thalamus, left middle frontal gyrus (MFG), bilateral mid cingulate
cortex (MCC), right putamen, and right insular cortex. An increase
in regional GM volume was observed in the left amygdala. For de-
tails, see Table 3 and Fig. 3.
Correlation analyses within the EndoPain were based on 16
patients because clinical pain data from 1 patient were missing.
GM volume decrease in the cingulate gyrus (GM values extracted
from the cluster in the MCC identified in the group comparison)
correlated with regional GM volume of the left thalamus
(r = 0.56, P = 0.024) and with the regional GM volume of the left
MFG (r = 0.60, P = 0.014). GM values extracted from the MCC clus-
ter correlated negatively with pain unpleasantness (r = 0.59,
P = 0.016); that is, the less GM volume, the more unpleasant pain
was perceived; surprisingly, it also correlated negatively with pres-
sure needed to elicit high pain (r = 0.60, P = 0.013); that is, the
less GM volume, the more pressure was needed to elicit a pain
score of 13.5 on the GBS. GM values extracted from the thalamus
cluster and from the left MFG cluster correlated with MCC GM val-
ues (see above) and with pain unpleasantness (rthalamus = 0.64,
P = 0.008; lMFG = 0.53, P = 0.037; also see Fig. 4). Finally, GM val-
ues extracted from the cluster found in the right posterior IC also
correlated negatively with pain unpleasantness (rIC = 0.59,
P = 0.017). Neither anxiety nor depression scores were significantly
correlated with GM values of any of the clusters. There was also no
significant correlation between pain duration and GM volume in
any cluster.
In the Endo£Pain group, decreased GM volume (relative to
HCs) was observed only in the right inferior temporal gyrus. Fur-
thermore, this group showed an increase in regional GM volume
in several regions, including the right periaqueductal gray (PAG),
right inferior frontal gyrus, and right MFG. For details, see Table
3 and Fig. 3. There was a trend for a positive correlation between
pressure needed to elicit mild pain (7.5 on the GBS) and regional
GM volume in the right PAG cluster (identified in the group com-
parison with HCs; r = 0.53, P = 0.042); that is, the higher the GM
values the more pressure was needed to elicit mild pain. Regional
GM values in the right MFG correlated positively with regional PAG
GM values (r = 0.54, P = 0.04) and also with pressure needed to eli-
cit low pain (0.5 on the GBS, r = 0.60, P = 0.019).
In the £EndoPain group, GM volume decrease was observed
in the left thalamus when compared to HCs. There was a highly sig-
nificant negative correlation between regional left thalamus vol-
ume and pain ratings during menstruation (r = 0.94, P = 0.003).
Again, there was no significant correlation between pain duration
and GM volume in any cluster in the £EndoPain group.
4. Discussion
The current study sought to investigate changes in regional
brain morphology in patients with CPP, with and without endome-
triosis, as an attempt to disentangle the interaction between
chronic pain, endometriosis, and changes in brain morphology. A
decrease in regional GM volume in the thalamus was found in
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S. As-Sanie et al. / PAIN 153 (2012) 1006–1014 1011

Table 3
Changes in regional brain morphology (gray matter).

Region Cluster size (number of voxels) z-Score (peak value) Coordinates (MNI)
x y z
EndoPain < age-matched HC
L thalamus 465 3.91 13 16 7
L middle frontal gyrus (MFG) 312 3.75 37 34 26
L/R cingulate gyrus (MCC) 478 3.36 2 11 30
3.44 4 2 40
R putamen 379 3.29 29 0 3
R insula 371 4.02 45 35 17
EndoPain > age-matched HC
L amygdala 206 3.76 21 1 23
Endo£Pain < age-matched HC
R inferior temporal gyrus 332 3.98 59 48 18
Endo£Pain > HC
R PAG 233 3.73 6 32 13
R inferior frontal gyrus (IFG) 460 4.87 37 31 10
R middle frontal gyrus (MFG) 211 4.08 31 39 32
£EndoPain < age-matched HC
L thalamus 1102 4.70⁄ 13 20 12

EndoPain, endometriosis with chronic pelvic pain; Endo£Pain, endometriosis without chronic pelvic pain; £EndoPain, chronic pelvic pain without endometriosis; HC,
healthy control; PAG, periaqueductal gray MNI, Montreal Neurological Institute.
All analyses were t-tests with age as covariate of no interest, extent threshold = 200 contiguous voxels, P < 0.001, ⁄ pseudo t statistics, L = left, R = right.

patients with CPP, regardless of the presence of endometriosis. Fur-
thermore, patients with CPP and endometriosis showed decreased
GM volume in the right posterior insula, the right putamen, and
the MCC. Decreases in GM in the thalamus, MCC, and IC correlated
with pain unpleasantness in this group. Endometriosis patients
without CPP showed no evidence of a GM decrease within the pain
system, instead, an increase in regional GM volume was observed
in the mesencephalon (PAG) and the right prefrontal cortex.
Our results are well in line with other VBM studies reporting
decreases in GM in chronic pain patients, including other pelvic
pain conditions, in regions of the pain system (thalamus, IC, CC)
and/or those involved in pain modulation (prefrontal cortex)
[6,8,10,33,40]. Interestingly, a similar pattern of regional GM de-
crease has been observed in patients suffering from irritable bowel
syndrome (IBS), with decreased volume in various cortical and
subcortical structures, such as the anterior CC, MCC, IC, prefrontal
cortex, putamen, and thalamus [6,8,34]. Seminowicz et al. de-
scribed decreases in GM volume in the thalamus bilaterally in
IBS patients, close to where thalamic GM decrease was found in
this study [34]. Although our images do not have sufficient resolu-
tion to distinguish nuclei, the thalamic GM decrease seems to in-
volve the medial nuclei. These nuclei are structurally connected
with the prefrontal cortex and the anterior IC, and have been pro-
posed to be part of a visceral pain network. Interestingly, in the
EndoPain group, regional GM volume in the thalamus corre-
lated with regional MCC volume (and both were negatively corre-
lated with pain unpleasantness), suggesting that pain in this cohort
involves a network [17]. It is conceivable that both pain syn-
dromes, CPP and IBS, share a common underlying pathophysiology
resulting in disturbed visceroception; that is, (re)organization of
the thalamus allows normally ‘‘silent’’ visceral/proprioceptive sig-
nals to be processed differently, gain (increased) access to higher
cortical structures, and be perceived as painful.
Particularly relevant to this study is the growing line of
evidence that altered brain morphology and function is already
present in patients with dysmenorrhea [40,41,44], which is often
reported prior to transitioning to CPP. Against this background,
dysmenorrhea can be considered a precursor stage for some
women who progress to CPP. For example, Vincent et al. reported
altered CNS response to noxious stimuli in women with dysmenor-
rhea that persists beyond the time of menstruation, when women
do not report pain [44]. Tu et al. described changes in regional
cerebral metabolism in women with dysmenorrhea in the thala-
mus bilaterally [41]. These women also displayed increases in
GM volume in the MCC, secondary somatosensory cortex, hippo-
campus, hypothalamus, and mesencephalon [40]. Interestingly,
the increase in the MCC projected near the cluster of GM decrease
found in our study, which has been described in other chronic pain
states [20,30]. Furthermore, the regional increase in GM in the
mesencephalon matched the increase in GM found in the
Endo£Pain group in the current study; both clusters projected
to the PAG, a key structure in the antinociceptive system. As such,
it is tempting to hypothesize that despite endometriosis serving as
a cyclic pain generator, the Endo£Pain group experienced little if
any (cyclic) pain, due to adaptive changes in the PAG, possibly due
to increased antinociceptive capacity. In support of this hypothesis,
we found that PAG volume showed a trend to be positively corre-
lated with pressure needed to elicit mild pain, suggesting a rela-
tionship between PAG volume and pressure pain thresholds.
4.1. Endometriosis, dysmenorrhea, and CPP – a conceptual approach to
pain chronification
Endometriosis is an important risk factor for CPP, and it is well
accepted that endometriosis can act as a nociceptive source and
peripheral pain generator during menses, often leading to cyclic
pelvic pain (dysmenorrhea). However, it remains unclear why only
some women undergo a transition to a chronic pain state, while
others do not. One might argue that endometriosis is the only
source of pain, and that the pain experienced in these women out-
side of the menses is due to an ongoing neuroinflammatory process
in the pelvis. In such a scenario, chronic pain is conceptually
understood as being the result of an ongoing nociceptive input (de-
fined here as a peripherally generated, neural input using nocicep-
tive pathways, such as C and Ad fiber) to an otherwise normal
brain. However, this hypothesis has recently been challenged by
several authors who summarize the increasing evidence that the
mechanism of pelvic pain in women with endometriosis may be
partly related to CNS amplification of pain processing [19,37]. This
process of central pain modulation (amplification or inhibition)
could explain why some women suffer from dysmenorrhea and/
or CPP but do not have an identifiable peripheral nociceptive input,
 Ò
1012 S. As-Sanie et al. / PAIN 153 (2012) 1006–1014

Fig. 3. Results from voxel-based morphometry analysis. Statistical parametric maps (SPM) demonstrating differences between groups (t-test with age as a covariate of no
interest). (A, B) Decreased gray matter volumes (in red) in the cingulate gyrus, the right putamen, and the left thalamus in the EndoPain group, as compared to healthy
controls. (C, D) Increased gray matter volume (in yellow) in the right periaqueductal gray (PAG) in the Endo£Pain group, as compared to healthy controls. (E, F) Decreased
gray matter volume (in red) in the left thalamus in the £EndoPain group as compared to healthy controls. P < 0.001, extent threshold = 200 contiguous voxels.

while other women with endometriosis (even severe) experience
little if any pain.
The hallmark of chronic pain seems to be a decrease in GM vol-
ume in structures known to be part of the pain system, although
increases in regional GM have been described in some studies,
mainly in the basal ganglia [31,33,47]. These changes in GM vol-
ume may vary between pain states and brain structures involved,
and each might depend on pain duration, pain occurrence (inter-
mittent vs. persistent), personality traits, and medication; as such,
the current literature is inconclusive. However, it is also possible
that GM changes are dynamic and change over time within an indi-
vidual. For example, some recent longitudinal studies suggest that
GM changes can be induced by repeated experimental pain [39],
and that changes associated with clinical pain can reverse sponta-
neously [25] and/or after removal of the nociceptive source [15].
Given that changes in regional brain morphology are not preexist-
ing in the few published longitudinal studies, but develop after re-
peated nociceptive input, it is possible that the initial ‘‘reaction’’ of
the brain is a GM increase in certain pain-transmitting areas, such
as the MCC and the somatosensory cortex, as well as changes in re-
gional metabolism (thalamus) [39–41]. This initial increase in GM
might at first be an adaptive mechanism. Dependent on the dura-
tion and persistence of the nociceptive input, local characteristics
of the neural tissue and other factors such as capacity/effectiveness
of antinociceptive systems, a transition to a chronic pain state
might then take place in some patients, which is marked by a de-
crease in regional gray matter volume in the pain system. These
changes, once they occur, may then contribute to an ongoing pain
perception, even after disappearance/removal of the initial noci-
ceptive source.
Whether pain becomes chronic depends on the interaction of
various factors, namely the persistence of the peripheral pain gen-
erator, the antinociceptive capacity, and (maladaptive) neuroplas-
ticity of the pain system. Given that dysmenorrhea is often a
 Ò
S. As-Sanie et al. / PAIN 153 (2012) 1006–1014
Fig. 4. Scatter plot: pain thalamic gray matter vs pain unpleasantness in the
EndoPain group. Correlation analysis between left thalamic gray matter (GM),
and pelvic pain unpleasantness ratings in the EndoPain group. GM values were
extracted from the cluster in the left thalamus identified in the group comparison
between the EndoPain group and healthy controls. GBS, Gracely Box Scale, pain
unpleasantness in last month.
pre-stage of CPP, our data and those of others suggest that pain
chronification is marked by a decrease in regional GM volume in
the pain system. Those women that remain relatively ‘‘pain-free,’’
on the other hand, do not show these decreases. In contrast, they
show an increase in GM volume in the antinociceptive system,
which again might be adaptive. A conceptual model summarizing
the possible relationship between dysmenorrhea and factors asso-
ciated with the progression to CPP is presented in Fig. 5.
4.2. Limitations
The group of £EndoPain patients was rather small (n = 6).
Although we tried to address this issue by performing nonparamet-
ric tests, a larger sample size is preferable. The small sample in this
subgroup is due to the fact that endometriosis is highly prevalent in
the CPP clinic that referred patients to this research protocol (70%-
80%), and the strict inclusion criteria that were required of this sub-
group. For obvious reasons, not all of the HCs had been explored via
laparoscopy. Given a general population prevalence of endometri-
osis of 5%-10%, we estimate that 1-2 HCs had undiagnosed endome-
triosis. However, given this small number and substantial
differences seen between patient and HC subgroups, we would
not expect this small misclassification error to significantly influ-
ence our results. Finally, the cross-sectional design of this study
precludes the ability to determine whether the changes in GM vol-
ume are a cause or consequence of the pain experience. Longitudi-
nal studies are needed to better address this important question.
4.3. Conclusions
The current study adds to the growing body of literature sug-
gesting that chronic pain states are associated with changes in re-
gional brain morphology. Our data challenge the idea of
endometriosis being the only and direct cause of pelvic pain in wo-
men with endometriosis-associated CPP, suggesting that central
mechanisms as reflected by changes in regional brain morphology,
such as thalamic GM decrease, play a pivotal role. Whether in the
wake of a prolonged nociceptive input (caused by endometriosis)
or preexisting, these central mechanisms seem to play a critical
role in the pain chronification process. As such, we suggest that
CPP in most women results from an interaction between antinoci-
ceptive capacity and central (mal)adaptive plasticity.
1013
A Pain generator
1.Peripheral factors (e.g. endometriosis)
2.Central factors *
1a
a
Dysmenorrhea
B (cyclic pain)
1b 1c
Initial changes in regional
brain morphology and/or
metabolism in the pain
system e.g. mid cingulate
cortex (MCC), PAG, etc.
2a 2b
D No (little) Pelvic Pain C Chronic Pelvic Pain
Adaptation of the pain system:
normalization GM volume in the
3 Maladaptation of the pain
system: decrease in GM volume
thalamus, insular cortex, in the thalamus, insular cortex
cingulate cortex; increase in the and MCC
PAG**
Fig. 5. Dysmenorrhea, endometriosis, and chronic pelvic pain (CPP) – a conceptual
approach to pain chronification. Possible mechanisms of pain chronification in
patients with dysmenorrhea and/or endometriosis. (A) Initially, a nociceptive
source serves as a ‘‘pain generator,’’ inducing cyclic pain (dysmenorrhea) and
associated changes in regional brain morphology and metabolism. A nociceptive
input can be created via sensitized nerve fibers surrounding endometriosis lesions
within the pelvis, nerve fiber proliferation in the uterus and/or endometrium
(which can also occur in the absence of endometriosis), prostaglandin-mediated
uterine contractions, or other peripheral abnormalities. ⁄ Central factors, such as
direct sex hormone–central nervous system interactions, may also act as pain
generators by sensitizing the brain to nociceptive neural input. (B) Dysmenorrhea
and initial changes in regional brain morphology and metabolism may remain
stable or may show further changes, either adaptive or maladaptive. (C) Those
women who progress to CPP show maladaptive changes in the pain system. Less
commonly, this may occur without a preceding phase of dysmenorrhea (arrow 1c).
(D) Those women who experience resolution of their dysmenorrhea (2a) or CPP (3),
and those who do not experience pelvic pain despite having a peripheral pain
generator (1b) show a ‘‘normalization’’ of or no change in gray matter (GM) volume
in the thalamus, insular cortex and cingulate cortex, but have an associated increase
in GM volume in the periaqueductal gray (PAG). ⁄⁄ Hypothetically, an increase in
GM volume in the PAG is associated with a gain of function of the antinociceptive
system. MCC, mid cingulate cortex.
Conflict of interest statement
D.J. Clauw declares associations with the following companies:
Cypress Bioscience, Eli Lilly and Company, Forest Laboratories,
Pierre Fabre Médicament, Pfizer, Procter & Gamble, Novu, Jazz,
Johnson and Johnson, Merck, and Wyeth Pharmaceuticals. See
the article online for full details of these relationships. The other
authors declare no competing interests. R. E. Harris has received
consulting fees and grant support from Pfizer.
Acknowledgments
This work was supported in part by the following research
grants: NIH Building Interdisciplinary Research in Women’s Health
K12HD001438, NIH UL1RR024986; Bayer Droegemueller Award in
Clinical Research, NIH R01-AR050044, and DAMD 17-00-2-0018.
Tobias Schmidt-Wilcke is currently supported by a grant from
the DFG (Deutsche Forschungsgemeinschaft, GZ: SchM 2665/1-1).
Richard Harris is supported by grants from the Dana Foundation
 Ò
1014 S. As-Sanie et al. / PAIN 153 (2012) 1006–1014
and the Department of Defense (Army Grant: DAMD-W81XWH-
07-2-0050). Vitaly Napadow and Jieun Kim were supported by
NCCAM, NIH (R01-AT004714 [Napadow], P01-AT002048 [Rosen]).
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